study to evaluate the efficacy safety and tolerability of qr-421a in subjects with rp due to mutations in exon 13 of the ush2a gene with early to moderate vision loss (celeste)

Conditions: Retinitis Pigmentosa; Usher Syndrome Type 2; Deaf Blind; Retinal Disease; Eye Diseases; Eye Diseases, Hereditary; Eye Disorders Congenital; Vision Disorders

Summary: the purpose of this study is to evaluate the efficacy safety and tolerability of qr-421a administered via intravitreal injection (ivt) in subjects with retinitis pigmentosa (rp) due to mutations in exon 13 of the ush2a gene with early to moderate vision loss.

the purpose of this study is to evaluate the efficacy safety and tolerability of qr-421a administered via intravitreal injection (ivt) in subjects with retinitis pigmentosa (rp) due to mutations in exon 13 of the ush2a gene with early to moderate vision loss. the below dose levels of qr-421a will be evaluated with the loading dose administered at day 1 and maintenance dose administered at month 3 and every 6 months thereafter: 1. loading dose of 180 μg, maintenance dose of 60 μg 2. loading dose of 60 μg, maintenance dose of 60 μg dose levels will include subjects randomized to sham-procedure or treatment with qr-421a. after the study eye has been treated for at least 12 months, treatment of the fellow eye and cross-over of subjects assigned to sham-procedure may be initiated in eligible eyes based on assessment of benefit-risk.

Eligibility criteria:
inclusion criteria: 1. male or female, ≥ 18 years of age or a minor (12 to \< 18 years) with permission from a parent or legal guardian. 2. an adult willing to comply with the protocol, follow study instructions, attend study visits as required and willing and able to complete all study assessments. or a minor able to complete all study assessments and comply with the protocol and has a parent or caregiver willing and able to follow study instructions, and attend study visits with the subject as required. 3. clinical presentation consistent with rp with usher syndrome type 2 or nonsyndromic form of rp (nsrp), based on ophthalmic, audiologic, and vestibular examinations. 4. a molecular diagnosis of homozygosity or compound heterozygosity for 1 or more pathogenic exon 13 mutations in the ush2a gene, based on genetic analysis at screening. 5. bcva better than ≥69 letters (approximate snellen equivalent 20/40) in the study eye, using the best bcva reading at screening. 6. impairment of visual field (vf) in the opinion of the investigator as determined by perimetry, with a continuous area of central field greater than or equal to 10 degrees diameter in each meridian as measured by a size v4e target, and a mean defect of ≥ 10 db, in the study eye. 7. clearly visible and measurable ellipsoid zone (ez) width and/or area on sdoct, per investigator judgement. 8. no limitations to sd-oct image collection that would prevent high quality, reliable images from being obtained in both eyes, as determined by the investigator. 9. reliable best corrected visual acuity (bcva), perimetry, and other measurements in both eyes, as described in the study reference manual and imaging manual and determined by the investigator. 10. no visually significant ocular media opacities and adequate pupillary dilation to permit good quality retinal imaging, as assessed by the investigator. exclusion criteria: 1. presence of additional non-exon 13 ush2a pathogenic mutation(s) on the ush2a allele carrying the exon 13 mutation in subjects who have monoallelic exon-13 mutations. 2. presence of non-exon 13 ush2a pathogenic mutation(s) on both ush2a alleles in subjects who have biallelic exon 13 mutations. 3. presence of pathogenic mutations in genes (other than the ush2a gene) associated with usher syndrome type 2 or nsrp, or other inherited retinal degenerative diseases or syndromes. note: the confirmed presence of homozygous or compound heterozygous known disease-causing mutations in other genes involved in recessive retinal dystrophies (rd), or the confirmed presence of known disease-causing mutations in genes involved in dominant or x-linked retinal dystrophies is exclusionary. 4. presence of any significant ocular or non-ocular disease/disorder (or medication and/or laboratory test abnormalities) which, in the opinion of the investigator and with concurrence of the medical monitor, may either put the subject at risk because of participation in the study, may influence the results of the study, or the subject's ability to participate in the study. this includes but is not limited to a subject who has uncontrolled cystoid macular edema (cme) in the study eye. cme is permissible if stable for 3 months (with or without treatment). past cme is permissible if resolved for more than 1 month. 5. history or presence of ocular herpetic diseases (including herpes simplex virus, varicella zoster or cytomegalovirus) in either eye. 6. presence of any active ocular infection in either eye. 7. presence of any of the following lens opacities in the study eye: cortical opacity ≥ +2, posterior subcapsular opacity ≥ +2, or a nuclear sclerosis ≥ +2, and which are: 1) clinically significant in the opinion of the investigator, 2) would adequately prevent clinical and photographic evaluation of the retina. 8. history of amblyopia in the study eye that resulted in significant vision loss, in the opinion of the investigator. 9. receipt within 3 months prior to screening of any intraocular or periocular surgery (including refractive surgery), or an ivt injection other or planned intraocular surgery or procedure during the course of the study. 10. current treatment or treatment within the past 12 months with therapies known to influence the immune system (including but not limited to steroid implants, cytostatics, interferons, tumor necrosis factor (tnf)-binding proteins, drugs acting on immunophilins, or antibodies with known impact on the immune system). subjects that have been treated with systemic steroids within the past 12 months or that require intermittent use of topical steroids may be considered for inclusion following approval by the medical monitor. 11. a history of glaucoma or an iop greater than 24 mmhg in either eye that is not controlled with medication or surgery. 12. use of any investigational drug or device within 90 days or 5 half-lives preceding the first dose of study medication, whichever is longer, or plans to participate in another study of an investigational drug or device during the course of the study. 13. any prior treatment with genetic or stem-cell therapy for ocular or non-ocular disease. 14. history of malignancy within 2 years prior to screening, except adequately treated squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. 15. known hypersensitivity to antisense oligonucleotides or any constituents of the injection. 16. pregnant and breastfeeding subjects. females of childbearing potential and males must comply with using highly effective methods of contraception as defined in the protocol. women of non-childbearing potential may be included without the use of adequate birth control.

Keywords: retinitis pigmentosa ush2a rp exon 13 rna therapies antisense oligonucleotide exon skipping celeste ivt mutations in exon 13 of the ush2a gene nsrp intravitreal injection non-syndromic rp inherited retinal diseases usher syndrome